Neurofibromatosis Type 1 and Autism Spectrum Disorder

Abstract

WHAT'S KNOWN ON THIS SUBJECT: NF1 is the commonest singlegene neurodevelopmental disorder with known neurobiology and developmental impact on attention and cognition. Its impact on social functioning is described but poorly understood, with no population-based study of autism spectrum disorder (ASD) prevalence in the disorder. WHAT THIS STUDY ADDS:This epidemiological study shows high prevalence of 25% ASD in NF1 not explained by learning difficulties. ASD should be considered during clinical practice with NF1. Further research into NF1 as a single-gene model of ASD is warranted.abstract OBJECTIVE: To determine the prevalence of autism spectrum disorder (ASD) in Neurofibromatosis Type 1 (NF1). METHODS:Second-phase population-based epidemiologic study using an allcase NF1 registry in a defined UK 4.1 million population area. A total of 109 (52.7%) of 207 responders from the initial screening phase were grouped by using the parent-rated Social Responsiveness Scale (SRS) as significant ASD (SRS$76; n 5 32), moderate ASD (SRS $ 60,76; n 5 29), or non-ASD (SRS ,60, n 5 48). Twenty-three cases from the significant ASD group, 16 from moderate ASD, and 8 from non-ASD (total n 5 47), invited proportionately by random selection, were seen for detailed confirmatory ascertainment. Assessments on Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Scale-Generic, and verbal IQ were combined by using standard Collaborative Program for Excellence in Autism criteria into an ASD categorization for each case (ASD, broad ASD with partial features, non-ASD). A preplanned weighted analysis was used to derive prevalence estimates for the whole population.RESULTS: Fourteen (29.5%) of 47 showed ASD, 13 (27.7%) broad ASD, and 20 (42.5%) non-ASD. The ASD/broad ASD group showed male predominance (1.7:1.0), but did not differ significantly from the non-ASD group on IQ, age, socioeconomic status, inheritance, physical severity, or education. The population prevalence estimate is 24.9% ASD (95% confidence interval 13.1%-42.1%) and 20.8% broad ASD (95% confidence interval 10.0%-38.1%); a total of 45.7% showing some ASD spectrum phenotype. Dr Garg contributed to the study design, identified the participants, led the study fieldwork, undertook preliminary analysis, and drafted the initial manuscript and revisions; Professor Green conceptualized the study, contributed to the design, supervised the fieldwork and early analysis, and critically reviewed and revised the manuscript; Dr Leadbitter contributed to the fieldwork assessments, data entry, and initial analysis, and contributed to drafting and critical review of the manuscript; Dr Emsley designed and carried out the analysis, and contributed to the drafting and critical review of the manuscript; Dr Lehtonen contributed to the initial design and patient identification; Dr Evans contributed to the initial design, supervised patient identification, and contributed to drafting and critical review of the manuscript; Dr Huson conceptualized the study, contributed to the design, super...

NF1 regulation of RAS/ERK signaling is required for appropriate granule neuron progenitor expansion and migration in cerebellar development

“…It has long been appreciated that individuals with Neurofibromatosis type 1, caused by germline mutation of the NF1 tumor suppressor, are at high risk for intellectual and/or cognitive deficits (Costa and Silva 2003;Hyman et al 2005;Samuels et al 2009). In the past, many of these claims have remained largely anecdotal; however, recent concerted efforts have confirmed these findings (Lorenzo et al 2013;Costa et al 2014) and revealed a high incidence of ASD among NF1 individuals (Garg et al 2013).…”

“…It has been estimated that between 30% and 70% of NF1 patients have learning disabilities (Hyman et al 2005). In addition, ;1% of children with autism spectrum disorders (ASDs) are eventually diagnosed with NF1 (Marui et al 2004), and more recent studies indicate a significant incidence of ASDs in NF1 individuals (Garg et al 2013). Genetically engineered mouse models (GEMMs) with heterozygous or conditional NF1 inactivation have behavioral phenotypes related to learning disabilities (Cui et al 2008).…”

Social Competence in Children with Neurofibromatosis Type 1: Relationships with Psychopathology and Cognitive Ability

“…Importantly, however, NF1 is associated with impairments in several domains that overlap with ASD (including delayed social, executive, and language skills), and so the true prevalence of ASD in NF1 may be lower than these reports would indicate [24]. Nevertheless, a recent population-based epidemiologic study of children and adolescents in with NF1 using diagnostic assessment tools estimated a population ASD prevalence of 24.9% [25], well above the estimated general population prevalence of 1.5% [26].…”

A theory inspired proposal for a novel medical treatment in autism. The cerebellar model of autism and the hypothesis of dorsal stream dysfunction: evidence from idiopathic and syndromic cases.

“…A prevalence of 25% comorbid ASD in NF1 was established in a recent epidemiological study (Garg et al 2013). Cerebellar hypoplasia in NF1 appears to have been underestimated (Toelle et al 2015) and another study showed a strong association between gait width and spatial working memory (Champion et al 2014).…”